Targeted molecular therapy is a landmark advance in the treatment of solid cancers. Gastrointestinal stromal tumor (GIST), the most common human sarcoma, has been a model for molecular therapy because it is driven primarily by either a Kit or Pdgfr? mutation, and the small molecule inhibitor imatinib mesylate is effective against both associated oncoproteins. Previously, we have shown that part of the anti-tumor efficacy of imatinib depends on altering the intratumoral immune response to promote T cell immunity. Our goal is to optimize the use of immune therapy with molecular therapy to achieve better oncologic outcomes. Current therapy of advanced GIST relies entirely on tyrosine kinase inhibitors, since conventional chemotherapy is ineffective. While imatinib is efficacious, its effects are usually short-lived as acquired resistance develops, usually due to an additional mutation in Kit. Furthermore, some patients with GIST have primary resistance to imatinib, as their tumor never responds to treatment. Therefore, novel treatments are needed. We have discovered that the transcription factors estrogen receptor alpha and beta-catenin are critical to tumor cell survival in mouse and human GIST. In this proposal, we will investigate estrogen receptor alpha and beta-catenin inhibition in imatinib-sensitive and imatinib-resistant GIST and combine it with immunotherapy to increase anti-tumor efficacy. We will utilize three genetically engineered mouse models of GIST, two of which contain imatinib-resistant Kit mutations. We will perform correlative immunologic studies on freshly procured human GIST surgical specimens. We expect that the results will advance our understanding of the biology of GIST and lead to novel clinical trials combining immune and molecular therapy. While we are focused on GIST, our findings will have relevance to other cancers treated with targeted therapy.